Hypolipidemic benzothiazepine compounds

ABSTRACT

The present invention is concerned with processes for preparing hypolipidaemic benzothiazepine compounds of formula (I) ##STR1## wherein l is an integer of from 0 to 4; m is an integer of from 0 to 5; n is an integer of from 0 to 2; R and R&#39; are atoms or groups independently selected from halogen, nitro, phenylalkoxy, C 1-4  alkoxy, C 1-6  alkyl and --O(CH 2 ) p  SO 3  R&#34; wherein p is an integer of from 1 to 4 and R&#34; is hydrogen or C 1-6  alkyl, wherein said phenylalkoxy, alkoxy and alkyl groups are optionally substituted by one or more halogen atoms; R 4  is C 1-6  straight alkyl group; and R 5  is a C 2-6  straight alkyl group; and their salts, solvates and physiologically functional derivatives; and intermediates useful in said processes.

This application is a division of application Ser. No. 08/290,805, filedDec. 5, 1994, now U.S. Pat. No. 5,663,165.

The present invention is concerned with new hypolipidaemic compounds,with processes and novel intermediates for their preparation, withpharmaceutical compositions containing them and with their use inmedicine, particularly in the prophylaxis and treatment ofhyperlipidaemic conditions, such as atherosclerosis.

Hypolipidaemic conditions are often associated with elevated plasmaconcentrations of low density lipoprotein (LDL) cholesterol and very lowdensity lipoprotein (VLDL) cholesterol. Such concentrations may bereduced by decreasing the absorption of bile acids from the intestine.One method by which this may be achieved is to inhibit the bile acidactive uptake system in the terminal ileum. Such inhibition stimulatesthe conversion of cholesterol to bile acid by the liver and theresulting increase in demand for cholesterol produces a correspondingincrease in the rate of clearance of LDL and VLDL cholesterol from theblood plasma or serum.

There has now been identified a novel class of heterocyclic compoundswhich reduce the plasma or serum concentrations of LDL and VLDLcholesterol and in consequence are particularly useful as hypolipidaemicagents. By decreasing the concentrations of cholesterol and cholesterolester in the plasma, the compounds of the present invention retard thebuild-up of atherosclerotic lesions and reduce the incidence of coronaryheat disease-related events. The latter are defined as cardiac eventsassociated with increased concentrations of cholesterol and cholesterolester in the plasma or serum.

For the purposes of this specification, a hyperlipidaemic conditions isdefined as any condition wherein the total cholesterol concentrations(LDL+VLDL) in the plasma or serum is greater than 240 mg/dL (6.21mmol/L) (J. Amer. Med. Assn. 256, 20, 2849-2858 (1986)).

U.S. Pat. No. 3,362,962 describes a genus of benzothiazepines outsidethe scope of the present invention which have muscle-relaxant andanticonvulsant activity; there is no disclosure in the patentspecification that the compounds described therein may be useful ashypolipidaemic agents.

According to the present invention, there is provided a compound offormula (I) ##STR2## wherein

l is an integer of from 0 to 4;

m is an integer of from 0 to 5;

n is an integer of from 0 to 2;

R and R' are atoms or groups independently selected from halogen, nitro,phenylalkoxy, C₁₋₄ alkoxy, C₁₋₆ alkyl and --O(CH₂)_(p) SO₃ R" wherein pis an integer of from 1 to 4 and R" is hydrogen or C₁₋₆ alkyl, whereinsaid phenylalkoxy, alkoxy and alkyl groups are optionally substituted byone or more halogen atoms;

R⁴ is a C₁₋₆ straight alkyl group; and

R⁵ is a C₂₋₆ straight alkyl group;

and salts, solvates and physiologically functional derivatives thereof.

Pharmaceutically acceptable salts are particularly suitable for medicalapplications because of their greater aqueous solubility relative to theparent, i.e. basic, compounds. Such salts must clearly have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds of the present inventioninclude those derived from inorganic acids, such as hydrochloric,hydrobromic, phosphoric, metaphosphoric, nitric, sulphonic and sulphuricacids, and organic acids, such as acetic, benzenesulphonic, benzoic,citric, ethanesulphonic, fumaric, gluconic, glycollic, isothionic,lactic, lactobionic, maleic, malic, methanesulphonic, succinic,p-toluenesulphinic, tartaric and trifluoroacetic acids. The chloridesalt is particularly preferred for medical purposes. Suitablepharmaceutically acceptable base salts include ammonium salts, alkalimetal salts, such as sodium and potassium salts, and alkaline earthsalts, such as magnesium and calcium salts.

Salts having a non-pharmaceutically acceptable anion are within thescope of the invention as useful intermediates for the preparation orpurification of pharmaceutically acceptable salts and/or for use innon-therapeutic, for example, in vitro, applications.

The term "physiologically functional derivative" as used herein refersto any physiologically acceptable derivative of a compound of thepresent invention, for example, an ester, which upon administration to amammal, such as a human, is capable of providing (directly orindirectly) such a compound or an active metabolite thereof.

A further aspect of the invention is prodrugs of the compounds of theinvention. Such prodrugs can be metabolised in vivo to give a compoundaccording to the invention. These prodrugs may or may not be active intheir own right.

The compounds of the present invention can also exist in differentpolymorphic forms, for example, amorphous and crystalline polymorphicforms. All polymorphic forms of the compounds of the present inventionare within the scope of the invention and are a further aspect thereof.

The term "alkyl" as used herein refers, unless otherwise stated, to amonovalent straight or branched chain radical. Likewise, the term"alkoxy" refers to a monovalent straight or branched chain radicalattached to the parent molecular moiety through an oxygen atom. The term"phenylalkoxy" refers to a monovalent phenyl group attached to adivalent C₁₋₆ alkylene group which is itself attached to the parentmolecular moiety through an oxygen atom.

The compounds of formula (I) may exist in forms wherein one or both ofthe carbon centres --C(R⁴)(R⁵)- and --CHPh(R')_(m) - (wherein Ph is thephenyl group) is/are chiral. The present invention includes within itsscope each possible optical isomer substantially free, i.e. associatedwith less than 5%, of any other optical isomer(s), and mixtures of oneor more optical isomers in any proportions, including racemic mixtures.

For the purposes of this specification, the absolute chiralities of theaforementioned carbon centres are given in the order --C(R⁴)(R⁵)-, then--CHPh(R')_(m) -. For example, the prefix "(RS)-" denotes an(R)-configuration at --C(R⁴)(R⁵)- and an (S)-configuration at--CHPh(R')_(m) - and the prefix "(RS,SR)-" denotes a mixture of twoisomers wherein one is (R)- at --C(R⁴)(R⁵)- and (S)- at --CHPh(R')_(m) -and the other is (S)- at --C(R⁴)(R⁵)- and (R)- at --CHPh(R')_(m) -.Other permutations will be clear to the skilled person.

In those cases where the absolute stereochemistry at --C(R⁴)(R⁵)- and--CHPh(R')_(m) - has not been determined, the compounds of the inventionare defined in terms of the relative positions of the R⁴ /R⁵ andH/Ph(R')_(m) substituents. Thus those compounds wherein the bulkier ofthe R⁴ and R⁵ substituents, i.e. the substituent of higher mass, and thePh(R')_(m) substituent are both located on the same side of thethiazepine ring are referred to herein as "cis", and those compounds inwhich they are located on opposite sides of the ring are referred to as"trans". It will be evident to a skilled person that both "cis" and"trans" compounds of the invention can each exist in two enantiomericforms which are individually designated "(+)-" or "(-)-" according tothe direction of rotation of a plane of polarised light when passedthrough a sample of the compound. Cis or trans compounds of theinvention in which the individual enantiomers have not been resolved arereferred to herein using the prefix "(+-)-".

Preferred compounds of formula (I) having particularly desirablehypolipidaemic properties include those wherein

n is 2;

R⁴ is methyl, ethyl, n-propyl, or n-butyl; and/or

R⁵ is ethyl, n-propyl, or n-butyl.

Of these, the (RR)-, (SS)-, and (RR,SS)-trans compounds are particularlypreferred.

A compound of formula (I) having exceptional hypolipidaemic propertiesis trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide in both its (RR)- and (RR,SS)-forms, viz(-)-(RR)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide and(+-)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide respectively. The former is especially preferred and isdepicted thus: ##STR3##

According to further aspects of the invention, there are also provided:

(a) compounds of formula (I) and pharmaceutically acceptable salts,solvates and physiologically functional derivatives thereof for use astherapeutic agents, particularly in the prophylaxis and treatment ofclinical conditions for which a bile acid uptake inhibitor is indicated,for example, a hyperlipidaemic condition, such as atherosclerosis;

(b) pharmaceutical compositions comprising a compound of formula (I) orone of its pharmaceutically acceptable salts, solvates, orphysiologically functional derivatives, at least one pharmaceuticallyacceptable carrier and, optionally, one or more other physiologicallyactive agents;

(c) the use of a compound of formula (I) or of a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof in the manufacture of a medicament for the prophylaxis ortreatment of a clinical condition for which a bile acid uptake inhibitoris indicated, for example, a hyperlipidaemic condition, such asatherosclerosis;

(d) a method of inhibiting the absorption of bile acids from theintestine of a mammal, such as a human, which comprises administering aneffective bile acid absorption inhibiting amount of a compound offormula (I) or of a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof to the mammal;

(e) a method of reducing the blood plasma or serum concentrations of LDLand VLDL cholesterol in a mammal, such as a human, which comprisesadministering an effective cholesterol reducing amount of a compound offormula (I) or of a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof to the mammal;

(f) a method of reducing the concentrations of cholesterol andcholesterol ester in the blood plasma or serum of a mammal, such as ahuman, which comprises administering an effective cholesterol andcholesterol ester reducing amount of a compound of formula (I) or of apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof to the mammal;

(g) a method of increasing the faecal excretion of bile acids in amammal, such as a human, which comprises administering an effective bileacid faecal excretion increasing amount of a compound of formula (I) orof a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof to the mammal;

(h) a method for the prophylaxis or treatment of a clinical condition ina mammal, such as a human, for which a bile acid uptake inhibitor isindicated, for example, a hyperlipidaemic condition, such asatherosclerosis, which comprises administering a therapeuticallyeffective amount of a compound of the formula (I), or of apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof to the mammal;

(i) a method of reducing the incidence of coronary heart disease-relatedevents in a mammal, such as a human, which comprises administering aneffective coronary heart disease-related events reducing amount of acompound of formula (I) or of a pharmaceutically acceptable salt,solvate, or physiologically functional derivative thereof;

(j) a method of reducing the concentration of cholesterol in the bloodplasma or serum of a mammal, such as a human, which comprisesadministering an effective cholesterol reducing amount of a compound offormula (I);

(k) processes for the preparation of compounds of formula (I) (includingsalts, solvates and physiologically functional derivatives thereof asdefined herein); and

(l) compounds of formula (II) for use as intermediates in thepreparation of compounds of formula (I).

Hereinafter all references to "compound(s) of formula (I)" refer tocompound(s) of formula (I) as described above together with their salts,solvates and physiologically functional derivatives as defined herein.

The amount of a compound of formula (I) which is required to achieve thedesired biological effect will, of course, depend on a number offactors, for example, the specific compound chosen, the use for which itis intended, the mode of administration and the clinical condition ofthe recipient. In general, a daily dose is in the range of from 0.3 mgto 100 mg (typically from 3 mg to 50 mg) per day per kilogrambodyweight, for example, 3-10 mg/kg/day. An intravenous dose can, forexample, be in the range of from 0.3 mg to 1.0 mg/kg, which canconveniently be administered as an infusion of from 10 ng to 100 ng perkilogram per minute. Infusion fluids suitable for this purpose cancontain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10mg, per millilitre. Unit doses can contain, for example, from 1 mg to 10g of the active compound. Thus ampoules for injection can contain, forexample, from 1 mg to 100 mg and orally administrable unit doseformulations, such as tablets or capsules, may contain, for example,from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case ofpharmaceutically acceptable salts, the weights indicated above refer tothe weight of the benzothiazepine ion derived from the salt.

For the prophylaxis or treatment of the conditions referred to above,the compounds of formula (I) can be used as the compound per se, but arepreferably presented with an acceptable carrier in the form of apharmaceutical composition. The carrier must, of course, be acceptablein the sense of being compatible with the other ingredients of thecomposition and must not be deleterious to the recipient. The carriercan be a solid or a liquid, or both, and is preferably formulated withthe compound as a unit-dose composition, for example, a tablet, whichcan contain from 0.05% to 95% by weight of the active compound. Otherpharmaceutically active substances can also be present including othercompounds of formula (I). The pharmaceutical compositions of theinvention can be prepared by any of the well known techniques ofpharmacy consisting essentially of admixing the components.

Pharmaceutical compositions according to the present invention includethose suitable for oral, rectal, tropical, buccal (e.g. sub-lingual) andparenteral (e.g. subcutaneous, intramuscular, intradermal, orintravenous) administration, although the most suitable route in anygiven case will depend on the nature and severity of the condition beingtreated and on the nature of the particular compound of formula (I)which is being used. Enteric-coated and enteric-coated controlledrelease formulations are also within the scope of the invention.Suitable enteric coatings include cellulose acetate phthalate,polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate andanionic polymers of methacrylic acid and methacrylic acid methyl ester.

Pharmaceutical compositions suitable for oral administration can bepresented in discrete units, such as capsules, cachets, lozenges, ortablets, each containing a predetermined amount of a compound of formula(I); as a powder or granules; as a solution or a suspension in anaqueous or non-aqueous liquid; or as an oil-in-water or water-in-oilemulsion. As indicated, such compositions can be prepared by anysuitable method of pharmacy which includes the step of bringing intoassociation the active compound and the carrier (which can constituteone or more accessory ingredients). In general, the compositions areprepared by uniformly and intimately admixing the active compound with aliquid or finely divided solid carrier, or both, and then, if necessary,shaping the product. For example, a tablet can be prepared bycompressing or moulding a powder or granules of the compound, optionallywith one or more accessory ingredients. Compressed tablets can beprepared by compressing, in a suitable machine, the compound in afree-flowing form, such as a powder or granules optionally mixed with abinder, lubricant, inert diluent and/or surface active/dispersingagent(s). Moulded tablets can be made by moulding, in a suitablemachine, the powdered compound moistened with an inert liquid diluent.

Pharmaceutical compositions suitable for buccal (sub-lingual)administration include lozenges comprising a compound of formula (I) ina flavoured base, usually sucrose and acacia or tragacanth, andpastilles comprising the compound in an inert base such as gelatin andglycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administrationconveniently comprise sterile aqueous preparations of a compound offormula (I), preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration can also be effected by means of subcutaneous,intramuscular, or intradermal injection. Such preparations canconveniently be prepared by admixing the compound with water andrendering the resulting solution sterile and isotonic with the blood.Injectable compositions according to the invention will generallycontain from 0.1 to 5% w/w of the active compound.

Pharmaceutical compositions suitable for rectal administration arepreferably presented as unit-dose suppositories. These can be preparedby admixing a compound of formula (I) with one or more conventionalsolid carriers, for example, cocoa butter, and then shaping theresulting mixture.

Pharmaceutical compositions suitable for topical applications to theskin preferably take the form of an ointment, cream, lotion, paste, gel,spray, aerosol, or oil. Carriers which can be used include vaseline,lanoline, polyethylene glycols, alcohols, and combinations of two ormore thereof. The active compound is generally present at aconcentration of from 0.1 to 15% w/w of the composition, for example,from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal administration can be presented as discretepatches adapted to remain in intimate contact with the epidermis of therecipient for a prolonged period of time. Such patches suitably containthe active compound in an optionally buffered, aqueous solution,dissolved and/or dispersed in an adhesive, or dispersed in a polymer. Asuitable concentration of the active compound is about 1% to 35%,preferably about 3% to 15%. As one particular possibility, the activecompound can be delivered from the patch by electrotransport oriontophoresis, for example, as described in Pharmaceutical Research,3(6), 318 (1986).

The compounds of the invention can be prepared by conventional methodsknown to a skilled person or in an analogous manner to processesdescribed in the art.

For example, compounds of formula (I) wherein n=0 can be prepared byreducing the imine bond of a compound of formula (II) ##STR4## whereinl, m, R, R', R⁴ and R⁵ are as hereinbefore defined, using, for example,a boron compound, such as borane, in a suitable solvent, such as THF, orcatalytic hydrogenation using, for example, a palladium catalyst, suchas 10% Pd/C.

Compounds of formula (II) as herein defined are considered to be noveland constitute a further aspect of the present invention.

Compounds of formula (II) can be prepared by cyclising compounds offormula (III) ##STR5## wherein l, m, R, R', R⁴ and R⁵ are ashereinbefore defined, by, for example, azeotropic distillation orrefluxing in the presence of a suitable drying agent, such as molecularsieves, in a suitable solvent, for example, 2,6-lutidine, in thepresence of an acid, such as HCl.

Compounds of formula (III) can be prepared by reacting a compound offormula (IV) ##STR6## wherein l, m, R and R' are as hereinbeforedefined, with a compound of formula (V) ##STR7## wherein R⁴ and R⁵ areas hereinbefore defined, typically in a polar solvent, for example,methanol.

Compounds of formula (III) can also be prepared by reacting a compoundof formula (XVIII) ##STR8## wherein l, m, R and R' are as hereinbeforedefined and L is a suitable leaving group, for example, halogen, with acompound of formula HSCH₂ C(R⁴)(R⁵)NH₂ wherein R⁴ and R⁵ are ashereinbefore defined.

Compounds of formula (XVIII) can be prepared by reacting a compound offormula (XIX) ##STR9## wherein l, L and R are as hereinbefore defined,with a compound of formula Ph(R')_(m) H wherein Ph is a phenyl group andm and R' are as hereinbefore defined, typically by a Friedel-Craftsreaction using, for example, aluminium chloride.

Compounds of formula (IV) can be prepared by reacting a compound offormula (VI) ##STR10## wherein l and R are as hereinbefore defined, witha compound of formula (R')_(m) PhCN wherein Ph is a phenyl group and mand R' are as hereinbefore defined. The reaction is typically carriedout by lithiation of compound (VI) using, for example, n-butyl lithiumin the presence of N,N,N',N'-tetramethylethylenediamine (TMEDA) followedby reaction with the appropriate benzonitrile in a non-polar solvent,for example, cyclohexane.

Compounds of formula (IV) can also be prepared by reacting a compound offormula (XVIII) as hereinbefore defined with sodium sulphide.

Compounds of formulae (V), (XIX), (VI) and (R')_(m) PhCN as hereinbeforedefined can be obtained commercially or prepared by method known tothose skilled in the art or obtainable from the chemical literature.Thus compounds of formula (V) can be prepared from the corresponding2-substituted 2-aminoethanols.

Compounds of formula (I) wherein n=0 can also be prepared by cyclising acompound of formula (VIII) ##STR11## wherein l, m, R, R', R⁴ and R⁵ areas hereinbefore defined and L' is halogen, for example, bromine, bytreatment with strong base, for example, n-butyl lithium, in a suitablesolvent, such as THF, at a low temperature, for example, -78° C.

Compounds of formula (VIII) can be prepared by reaction of a compound offormula (IX) ##STR12## wherein l, L', R, R⁴ and R⁵ are as hereinbeforedefined, with a compound of formula (R')_(m) PhCHO wherein Ph is aphenyl group and m and R' are as hereinbefore defined. The reaction istypically carried out in a non-polar solvent, for example, toluene, inthe presence of an acid, such as p-toluenesulphonic acid.

Compounds of formula (IX) can be prepared by reacting a compound offormula (XI) ##STR13## wherein l, L' and R are as hereinbefore defined,with a compound of formula (V) wherein R⁴ and R⁵ are as hereinbeforedefined, typically in a polar solvent, such as methanol.

Compounds of formula (IX) can also be prepared by reacting a compound offormula (XI) as hereinbefore defined with a compound of formula (XVII)##STR14## wherein R⁴ and R⁵ are as hereinbefore defined, in the presenceof a Lewis acid, for example, lithium chloride, at an elevatedtemperature, such as 170°-210° C.

Compounds of formulae (R')_(m) PhCHO as hereinbefore defined, (XI) and(XVII) can be obtained commercially or prepared by methods known tothose skilled in the art or obtainable from the chemical literature.Thus compounds of formula (XI) may be prepared from the correspondingdisulphides and compounds of formula (XVII) from the corresponding2-substituted 2-aminoethanols.

Compounds of formula (I) wherein n=0 can also be obtained by phenylatinga compound of formula (XIII) ##STR15## wherein l, R, R⁴ and R⁵ are ashereinbefore defined, using, for example, an organometallic compound,such as (R')_(m) PhLi, (R')_(m) PhCu, (R')_(m) PhZn, or (R')_(m) PhMgBrwherein Ph is a phenyl group and m and R' are as hereinbefore defined.

Compounds of formula (XIII) can be prepared by dehydrogenating thecorresponding compound of formula (XIV) ##STR16## wherein l, R, R⁴ andR⁵ are as hereinbefore defined, using, for example, an oxidising agent,such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), in a suitablesolvent, for example, toluene.

Compounds of formula (XIV) can be prepared by reducing the amidecarbonyl group of the corresponding compound of formula (XV) ##STR17##wherein l, R, R⁴ and R⁵ are as hereinbefore defined, using, for example,lithium aluminium hydride.

compounds of formula (XV) can be prepared by reacting a compound offormula (XVI) ##STR18## wherein l and R are as hereinbefore defined andZ is C₁₋₄ alkoxy, for example, methoxy, with a compound of formula (V)wherein R⁴ and R⁵ are as hereinbefore defined.

The compound of formula (XVI) wherein l=0 can be prepared fromcommercially available 2,2'-dithiosalicyclic acid by methods known tothose skilled in the art. Compounds of formula (XVI) wherein l≠0 can beobtained commercially or prepared by methods known to those skilled inthe art or obtainable from the chemical literature.

Compounds of formula (I) wherein n=1 or 2 can be prepared by oxidationof the corresponding compound of formula (I) wherein n=0 or by oxidationof the corresponding compound of formula (III) wherein n=0 prior tocyclisation and reduction to the compound of formula (I) using suitableoxidation conditions, for example, in the case wherein n is to be 2, 30%aqu. H₂ O₂ in the presence of trifluoroacetic acid.

Individual optical isomers of compounds of formula (I) substantiallyfree, of other optical isomers can be obtained either by chiralsynthesis, for example, by the use of the appropriate chiral startingmaterial(s), such as the aziridine (V), or by resolution of the productsobtained from achiral syntheses, for example, by chiral hplc.

Optional conversion of a compound of formula (I) to a corresponding acidaddition salt may be effected by reaction with a solution of theappropriate acid, for example, one of those recited earlier. Optionalconversion to a corresponding base salt may be effected by reaction witha solution of the appropriate base, for example, sodium hydroxide.Optional conversion to a physiologically functional derivative, such asan ester, can be carried out by methods known to those skilled in theart or obtainable from the chemical literature.

For a better understanding of the invention, the following Examples aregiven by way of illustration and are not to be construed in any way aslimiting the scope of the invention.

SYNTHETIC EXAMPLE 1

Preparation of(-)-(RR)-3-butyl-3-ethyl-2,3,4,5-terahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide

(a) Ethyl 2-aminobutyrate hydrochloride

A slurry of 2-aminobutyric acid (100 g, Aldrich) in absolute ethanol(300 ml) was stirred under nitrogen at 0° C. and thionyl chloride(120.79 g) was added dropwise. The reaction was stirred overnight at 0°C. and then gradually warmed to room temperature. The resulting whiteslurry was heated under reflux for 3 hours, left to cool for 10 minutes,then poured into chilled diethyl ether (600 ml) with hand stirring. Thesuspension was filtered and the solid product dried to give the desiredproduct (150 g) as a white solid. ¹ H NMR consistent with proposedstructure.

(b) Ethyl 2-benzylideneaminobutyrate

A solution of the product from step (a) (149.57 g), magnesium sulphate(74.32 g), and triethylamine (246 ml) in dichloromethane (1500 ml) wasstirred at room temperature under nitrogen and benzaldehyde (94.91 g,Aldrich) was added dropwise. The mixture was stirred at room temperaturefor 3 hours then filtered. The filtrate was concentrated, triturated indiethyl ether, filtered and concentrated to yield the desired product asa yellow oil (174 g). ¹ H NMR consistent with the proposed structure.

(c) Ethyl 2-benzylideneamino-2-ethylhexanoate

Sodium hydride (32.49 g, 60% dispersion in oil) andN,N-Dimethylformamide (DMF) (700 ml) were stirred under nitrogen at roomtemperature and a solution of the product from (b) (178.13 g) in DMF wasadded dropwise. After 2 hours stirring at room temperature, a solutionof butyl iodide (149.48 g) in DMF was added dropwise and the reactionleft stirring for a further 2 hours. The reaction was poured into an icecold mixture of water (560 ml), diethyl ether (300 ml) and ammoniumchloride (120 g). The resulting organic layer was dried over potassiumcarbonate then concentrated to give the desired product as a brown oil(220 g).

(d) Ethyl 2-amino-2-ethylhexanoate

The product from (c) (233.02 g) was partitioned between petroleum etherand 10% w/w hydrochloric acid (421 ml) and stirred at room temperaturefor 2 hours. The aqueous layer was extracted twice with petroleum etherand then chilled with ethyl acetate in an ice-salt bath. Sodiumhydroxide pellets were added to the mixture until the aqueous layer wasat pH 10. The latter was extracted twice with ethyl acetate and thecombined ethyl acetate layers were dried over potassium carbonate, thenconcentrated and vacuum distilled to give the desired product as acolourless oil. ¹ H NMR consistent with the proposed structure.

(e) 2-Amino-2-ethylhexan-1-ol

Lithium aluminium hydride (22.22 g) was added to anhydrous diethyl ether(450 ml) under nitrogen. The product from (d) (129.0 g) was diluted withdiethyl ether (40 ml) and added dropwise. The reaction was refluxed for1 hour then cooled to room temperature. 1M sodium hydroxide (23 ml) wasadded dropwise followed by deionised water. The resulting suspension wasfiltered and the filtrate concentrated to give the desired product as acolourless oil (87.9 g). ¹ H NMR consistent with the proposed structure.

(f) 2-Butyl-2-ethylaziridine

Acetonitrile (150 ml) and the product from (e) (20.0 g) were mixed undernitrogen, cooled to 2°-3° C. and chlorosulphonic acid (16.04 g, Aldrich)was added dropwise keeping the temperature below 10° C. The coolant wasremoved and the slurry left to stir for 80 minutes at room temperature.The reaction was concentrated in vacuo and co-distilled with water (50ml). 50% Aqueous sodium hydroxide (55.2 g) and water (50 ml) were addedand the mixture was distilled at atmospheric pressure. The organic layerwas collected from the distillate and dried with solid potassiumhydroxide to give the desired product (12.8 g). ¹ H NMR consistent withproposed structure.

(g) 2-Thiobenzophenone

A solution of N,N,N',N'-tetramethylethylenediamine (TMEDA) (104.6 g) incyclohexane (500 ml) was cooled and 2.5M n-butyl lithium (360 ml) wasadded. A solution of thiophenol (50.0 g) in cyclohexane (100 ml) wasadded slowly to the butyl lithium solution and the reaction was stirredat room temperature overnight. Benzonitrile (46.4 g, Aldrich) incyclohexane (100 ml) was added to give a slurry which was stirredovernight at room temperature. Water (500 ml) was added and the mixturestirred for 30 minutes then the aqueous layer was separated and treatedwith solid sodium hydroxide to give pH 14. The solution was boiled for90 minutes, cooled to room temperature and acidified to pH 1-2 withconc. HCl. The acidic solution was extracted with dichloromethane andthe combined extracts dried, then concentrated to give a red oil. Theoil was treated with 1M aqu. NaOH, extracted with dichloromethane andthe aqueous layer separated and treated with conc. HCl acid to give anoil. The oil was extracted into dichloromethane and the combinedextracts dried, then concentrated to give the desired product as anorange-red oil (83.4 g). ¹ H NMR consistent with proposed structure.

(h) 2-(2-Amino-2-ethylhexylthio)benzophenone

The product from (g) was dissolved in methanol (to a total volume of 250ml) and an equimolar amount of the product from (f) in methanol (totalvolume 120 ml) was added over 20 minutes. The mixture was stirred atroom temperature for 75 minutes then concentrated in vacuo to give adark red oil. This oil was taken up in diethyl ether (400 ml) andfiltered to remove contaminating solids. The desired product was left asa solution in ether for use in (i). ¹ H NMR consistent with proposedstructure.

(i) 3-Ethyl-3-butyl-5-phenyl-2,3-dihydrobenzothiazepine

1M Ethereal hydrochloric acid (275 ml) was added to a solution of theproduct from (h) (85.0 g) in diethyl ether and the mixture wasconcentrated in vacuo. The residue was azeotropically distilled byaddition of 2,6-lutidine (175 ml) and refluxing in a Dean-Starkapparatus overnight. The mixture was concentrated in vacuo, neutralisedby addition of 5% sodium bicarbonate then the minimum volume of ethylacetate was added to dissolve the red oil. The organic layer wasseparated, washed with brine, dried and concentrated. The crude residuewas purified by column chromatography on silica using toluene as eluant.Concentration of the relevant fractions gave the desired product (63.7g). ¹ H NMR consistent with the proposed structure.

(j)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine

1M Diborane (211 ml in THF) was added over 45 minutes to a solution ofthe product from (i) (63.7 g) in THF under nitrogen. Reaction wasstirred at room temperature for 17 hours. 50% Hydrochloric acid (125 ml)was added and the mixture was concentrated in vacuo. The residue waspartitioned between aqu. NaOH and ethyl acetate. The organic layer wasdried and concentrated to give an orange-yellow oil (67.5 g) comprisingcis and trans isomers which was chromatographed on silica using tolueneas eluant to give the desired product as a pale yellow oil (27.3 g). ¹ HNMR consistent with the proposed structure.

(k)(+-)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide

30% Aqueous hydrogen peroxide (73.1 g) and trifluoroacetic acid (TFA)(225 ml) were cooled and a solution of the product from (j) (70.0 g) inTFA (200 ml) was added. The reaction was stirred at room temperature for24 hours, then added to water (1000 ml) and basified with solid sodiumhydroxide. The resulting insoluble solid was filtered off, warmed with1M aqu. NaOH and extracted into ethyl acetate. The combined extractswere evaporated in vacuo to give the desired product (69.0 g). ¹ H NMRconsistent with the proposed structure.

(l)(-)-(RR)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide

The product from (k) (208.3 g) was mixed with diethyl ether (1500 ml)and (-)-di-p-toluoyl-L-tartaric acid (225.2 g, Schweitzerhall) indiethyl ether added. On standing, a white solid precipitated which wasfiltered off and recrystallised from acetone/hexane to give the desiredproduct is the acid salt. The title compound was liberated from its saltby treatment with 1M aqu. NaOH and extracted with ethyl acetate. Thecombined extracts were evaporated in vacuo to give the desired productas a white solid (83.0 g), mp 115°-116° C.

Analysis: Calcd. C 70.55; H 7.61; N 3.92; S 8.97

Found: C 70.58; H 7.56; N 3.96; S 8.88

¹ H NMR (DMSO-d₆), δ: 0.81-0.92 (6H, m, 2×CH₃); 1.15-1.40 (4H, m,2×CH₂); 1.47-1.70 (3H, m, CH₂ +NH); 1.80-1.90 (1H, m, CH₂); 2.13-2.24(1H, m, CH₂); 3.07-3.46 (2H, q, CH₂ SO₂); 6.09 (1H, s, CH); 6.71-6.74(1H, m, Ar-H); 7.26-7.41 (7H, m, Ar-H); 8.10-8.13 (1H, m, Ar-H)

Alternative preparation of(-)-(RR)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide

(a) Ethyl 2-aminobutyrate hydrochloride

Thionyl chloride (1.25 moles) was added to a solution of 2-aminobutyricacid (1 mole) in SD12A3 (95% ethanol/5% toluene) at a temperature of <5°C. When addition was complete, the mixture was stirred at 27° C. for 16hours and the resulting precipitate filtered off and washed with methylt-butyl ether to give the desired product as a white solid (97% yield).

(b) Ethyl 2-benzylideneaminobutyrate

Triethylamine (2 moles) was added to a solution of the product from step(a) (1 mole) in toluene. When addition was complete, benzaldehyde (1mole) was added. The mixture was azeotroped until no further water wascollected, then cooled to room temperature and filtered. The filtratewas evaporated in vacuo ti give the desired product as an oil.

(c) Ethyl 2-benzylideneamino-2-ethylhexanoate

A 1.6M solution of n-butyl lithium in hexane (33 mmoles, Aldrich) wasadded to a solution of diisopropylamine (40 mmoles) in THF (21 ml) at atemperature of 5°-10° C. When addition was complete, the mixture wasadded to a solution of the product from step (b) (30 mmoles) in THF (20ml) at a temperature of 5°-10° C. When addition was complete, n-butyliodide (40 mmoles) was added and the mixture allowed to warm to roomtemperature. After 20 hours, the mixture was poured into water/diethylether (1.1 L/0.5 L) and the organic layer separated, washed with brine(1.1 L), dried and evaporated in vacuo to give the desired product as anamber liquid (100% yield).

(d) Ethyl 2-amino-2-ethylhexanoate

A solution of the product from step (c) (1mole) in 1N aqu. HCl (1.2moles) was stirred for 10 minutes at room temperature, then washed withtoluene. The pH of the remaining aqueous phase was adjusted to 7 using12.5% w/v sodium hydroxide, then cooled to 10° C., further basified topH 12 and extracted with toluene. The extracts were combined, washedwith brine, dried and evaporated in vacuo. The residue was distilled togive the desired product as an oil (70-80% yield).

(e) (R)-2-Amino-2-ethylhexanoic acid

A suspension of pig liver esterase (0.1 g, Sigma-Aldrich-Fluka) in waterwas added to an aqueous solution of the product from step (d) (100 g).When addition was complete, the pH of the mixture was adjusted to 9.7using 1N aqu. NaOH and maintained at this value by the addition offurther 1N aqu. NaOH. After the addition of a predetermined amount of 1Naqu. NaOH (85 g over 10 hours), the mixture was washed with diethylether to remove unreacted (S)-ethyl 2-amino-2-ethyl-hexanoate. Theremaining aqueous phase was evaporated in vacuo to give a white solidcomprising the desired product and its sodium salt (40-45% yield).

(f) (R)-2-Amino-2-ethylhexan-1-ol

The product from step (e) (20 g) was added to a 1M solution of lithiumaluminium hydride (1.5 molar equivalents) in THF and the mixturereflexed for 3 hours, then stirred for 16 hours at room temperature. Themixture was cooled to about 0° C., then quenched with water and 1N aqu.NaOH added. The resulting solid was broken up with additional water andthe suspension heated at 50° C. for 5 minutes, then cooled to roomtemperature, diethyl ether (100 ml) added and filtered. The filtrate wasevaporated in vacuo to give the desired product as an oil (82% yield).

(g) (R)-2-Butyl-2-ethylaziridine

Chlorosulphonic acid (1 molar equivalent) was added to a solution of theproduct from step (f) (15 g) in dichloroethane (90 ml) at a temperatureof <16° C. When addition was complete, the mixture was stirred for 2hours at room temperature and then evaporated in vacuo. Water (60 ml)and 5% w/v aqu. NaOH (41 ml) were added and the mixture distilled atatmospheric pressure. The organic phase of the distillate was separatedand dried over KOH to give a solution of the desired product (77%yield).

(h) 2-Thiobenzophenone

A 2.5M solution of n-butyl lithium (2 moles) in hexane was added to asolution of N,N,N',N'-tetramethylethylenediamine (TMEDA, 2 moles) incyclohexane at a temperature of -8° to 0° C. When addition was complete,a 4.5M solution of thiophenol (1 mole) in cyclohexane was added and thetemperature allowed to rise to 40°-50° C. When addition was complete,the mixture was stirred overnight at room temperature. A 4.5M solutionof benzonitrile (1 mole) in cyclohexane was then added over 1 hour at atemperature of 15°-20° C. When addition was complete, the mixture washeated at 40° C. for 4 hours, then stirred at room temperature for 72hours and quenched with water. The resulting organic phase was extractedwith 1N sodium hydroxide and the combined extracts heated at 75° C. for2.5 hours, then cooled to room temperature, acidified to pH 1 usingconc. HCl and extracted four times with toluene. The combined extractswere dried and evaporated in vacuo to give a red oil which was taken upin SD3A and stirred at room temperature for 16 hours. The resultingprecipitate was filtered off and washed with SD3A to give the desiredproduct as a white solid (61% yield).

(i) (R)-3-Ethyl-3-butyl-5-phenyl-2,3-dihydrobenzothiazepine

The solution from step (g) (1.05 moles) was added to a suspension of theproduct from step (h) (1 mole) in 2,6-lutidine (50 ml) at a temperatureof about 25° C. When addition was complete, the mixture was stirred atroom temperature for 1.5 hours, then conc. HCl (6.3 ml) added. Whenaddition was complete, the mixture was azeotroped for 3 hours, thenstirred at room temperature overnight and evaporated in vacuo. Theresidue was taken up in 5% w/v aqu. NaHCO₃ and the solution extractedtwice with ethyl acetate. The combined extracts were washed with brine,dried and evaporated in vacuo. The residue was chromatographed in silicagel using 95:5 hexane:ethyl acetate as eluant to give the desiredproduct as a red-orange oil (77% yield).

(j)(RR,RS)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine

A 1M solution of diborane in THF (63 ml) was added to a solution of theproduct from step (i) (0.9 molar equivalents) in THF (100 ml) at atemperature of about 1° C. When addition was complete, the mixture wasstirred overnight at room temperature, then cooled to about 0° C. and50% v/v HCl (40 ml) added. When addition was complete, the mixture wasstirred at room temperature for 1 hour, then concentrated in vacuo toremove the THF. Water (25 ml) was added to the remaining aqueous phase,the pH adjusted to 8 using 12% w/v aqu. NaOH and the solution extractedwith ethyl acetate. The combined extracts were dried and evaporated invacuo to give the desired product as a red-orange oil comprising cis andtrans isomers (100% yield).

(k)(RR,RS)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide

A suspension of the product from step (j) (0.33 molar equivalents) intrifluoroacetic acid (25 ml) was added to a solution of 30% aqu. H₂ O₂(10.2 ml) in trifluoroacetic acid (20 ml) at a temperature of about 0°C. When addition was complete, the mixture was stirred overnight at roomtemperature, then poured into water (200 ml) to give a waxy solid whichwas separated and taken up in 1N aqu. NaOH. The solution was heated to40° C. then cooled and extracted with ethyl acetate. The combinedextracts were washed with 1N aqu. NaOH, dried and evaporated in vacuo togive an oil comprising the cis and trans isomers (84% yield).

(l)(-)-(RR)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide

A solution of (-)-di-p-toluoyl-L-tartaric acid (1 mole) in diethyl ether(20 ml) was added to a solution of the product from step (k) (1 mole) indiethyl ether (20 ml). When addition was complete, the mixture wasstirred at room temperature for 2 hours and the resulting crystalsfiltered off, washed with diethyl ether and dried to give the(RR)-tartrate salt which was neutralised with 1N aqu. NaOH and extractedwith ethyl acetate. The combined extracts were dried and evaporated invacuo to give an oil which crystallised from hot hexanes to give thedesired product as a white solid (58% yield). The mp, elemental analysisand ¹ H NMR of the product were in agreement with those obtained by thealternative synthesis.

Preparation of(-)-(RR)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide hydrochloride

The product from Synthetic Example 1 (0.95 g) was taken up in ether (75ml), 10M ethereal HCl (50 ml) added and the mixture stood for 3 hours.The resulting precipitate was filtered off and dried to give the desiredproduct as a white solid (0.86 g), mp 184°-188° C.

Analysis: Calcd. C 64.02; H 7.16; N 3.56; S 8.14

Found: C64.09; H 7.16; N 3.01; S 8.21

¹ H NMR (DMSO-d₆), δ: 0.8-0.91 (6H, m, CH₃); 1.00-1.04 (1H, m, CH₂);1.29 (3H, b, CH₂); 1.92-2.00 (3H, b, CH₂); 2.50-2.51 (3H, b, CH₂ +NH₂);3.40-4.80 (4H, b, CH₂ SO₂); 6.20 (1H, b, CH); 6.83 (1H, b, Ar-H);7.56-7.70 (7H, b, Ar-H); 8.10 (1H, b, Ar-H)

SYNTHETIC EXAMPLES 2-64

Each of the following compounds of formula (I) was prepared by a methodanalogous to that of Synthetic Example 1 or by one of the othersynthetic routes described herein. In all cases, ¹ H NMR and elementalanalysis were consistent with the proposed structure.

2)(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 98°-100° C.;

(-)-Trans-3-Methyl-3-propyl-2,3,4,5tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 129°-130° C.;

4) 3-Ethyl-3-methyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine, mp124°-125° C.;

5) (+)-3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 100°-102° C.;

6) 3-Butyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 103°-104° C.;

7) 3-Methyl-3-propyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 120°-121° C.;

8) 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 115°-116° C.;

9)(+)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide,mp 101° C.;

10)(+)-Trans-2,3,4,5-Tetrahydro-3-methyl-5-phenyl-3-propyl-1,4-benzothiazepine1,1-dioxide, mp 129°-130° C.;

11) (-)-3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 101°-103° C.;

12) 3-Ethyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepine, mp110°-112° C.;

13) 3-Ethyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepinehydrochloride 0.25 H₂ O, mp 162°-164° C. (eff.);

14) 3-Ethyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 128°-129° C.;

15) 3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepinehydrochloride, mp 211°-214° C.;

16)(+-)-2,3,4,5-Tetrahydro-3-methyl-5-phenyl-3-propyl-1,4-benzothiazepine,mp 101°-103° C.;

17) 2,3,4,5-Tetrahydro-3-methyl-5phenyl-3-propyl-1,4-benzothiazepine, mp72°-74° C.;

18) 3-Ethyl-2,3,4,5-tetrahydro-5-phenyl-3-propyl-1,4-benzothiazepinehydrochloride 0.25 H₂ O, mp 205°-207° C.;

19) 3-Ethyl-2,3,4,5-tetrahydro-5-phenyl-3-propyl-1,4-benzothiazepine1,1-dioxide 0.25 H₂ O, mp 115°-118° C.;

20) 2,3,4,5-Tetrahydro-5-phenyl-3,3-dipropyl-1,4-benzothiazepinehydrochloride, 209°-211° C.;

21) 3-Ethyl-2,3,4,5-tetrahydro-5-phenyl-3-propyl-1,4-benzothiazepine1,1-dioxide hydrochloride 0.33 H₂ O, 206°-209° C.;

22) 2,3,4,5-Tetrahydro-5-phenyl-3,3-dipropyl-1,4-benzothiazepine1,1-dioxide, mp 104°-106° C.;

23) 3,3-Dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepinehydrochloride, mp 209°-212° C.;

24) 3-Butyl-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1,4-benzothiazepinehydrochloride, mp 203°-205° C.;

25) 3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepinehydrochloride, mp 205°-207° C.;

26) 3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide hydrochloride, mp 209°-212° C.;

27) 2,3,4,5-Tetrahydro-3-methyl-3-pentyl-5phenyl-1,4-benzothiazepinemaleate, mp 182°-183° C.;

28) 3-Ethyl-2,3,4,5-tetrahydro-5-phenyl-3-propyl-1,4-benzothiazepinehydrochloride, mp 198°-200° C.;

29)(+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methyl-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 138°-140° C.;

30)(+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepine,light yellow oil;

(31)(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepine,light yellow oil;

32)(+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4benzothiazepine1,1-dioxide, mp 113°-115° C.;

33)(--)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepine1-oxide, mp 103°-105° C.;

34)(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepine1-dioxide hydrochloride, mp 199°-201° C.;

35)(+-)-Trans-3-Butyl-3-ethyl-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1-oxide, mp 98°-101° C.;

36)(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4benzothiazepine1-oxide, mp 133°-136° C.;

37)(+-)-Cis-7-Chloro-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine0.4 toluene, light yellow oil;

38)(+-)-Trans-7-Chloro-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine0.3 toluene, light yellow oil;

39)(--)-Trans-3-Butyl-7-Chloro-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 100°-102° C.;

40)(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-1,4-benzothiazepine1,1-dioxide hydrochloride, mp 194°-196° C.;

41)(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-tolyl)-1,4-benzothiazepine1,1-dioxide hydrochloride, mp 204°-206° C.;

42)(+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-tolyl)-1,4-benzothiazepine1,1-dioxide, mp 155°-156° C.;

43)(+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-1,4-benzothiazepine,mp 75°-77° C.;

44)(+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-methoxyphenyl)-1,4-benzothiazepine1,1-dioxide, mp 109°-111° C.;

45)(+-)-Cis-3-Butyl-3-ethyl-5-(4-fluorophenyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine,mp 76°-78° C.;

46)(+-)-Trans-3-Butyl-5-(3,4-dichlorophenyl)-3-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepine,mp 98°-100° C.;

47)(+-)-Trans-3-Butyl-5-(4-chlorophenyl)-3-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide hydrochloride 0.3 H₂ O, mp 178°-180° C.;

48)(+-)-Cis-3-Butyl-5-(4-chlorophenyl)-5-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide hydrochloride, mp 186°-188° C.;

49)Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(3-nitrophenyl)-1,4-benzothiazepine1,1-dioxide, mp 139°-142° C.;

50)Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-nitrophenyl)-1,4-benzothiazepine1,1-dioxide, mp 139°-142° C.;

51)(+-)-Trans-5-(4-Benzyloxyphenyl)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide, mp 94°-95° C.;

52)(+-)-Cis-5-(4-Benzyloxyphenyl)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepine1,1-dioxide, mp 137°-138° C.;

53)(+-)-Trans-5-(4-Benzyloxyphenyl)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepine,mp 97°-98° C.;

54)(+-)-Trans-3-(4-(3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,4-benzothiazepine-5-yl)phenoxy)propanesulphonicacid 1,1-dioxide, mp 270° C. (dec.);

55)(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(2-fluorophenyl)-1,4-benzothiazepine1,1-dioxide, hydrochloride, mp 194°-196° C.;

56)(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(3-fluorophenyl)-1,4-benzothiazepine1,1-dioxide, mp 143°-145° C.;

57)(+-)-Cis-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-pyridyl)-1,4-benzothiazepine1,1-dioxide, mp 121°-123° C.;

58)(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(4-pyridyl)-1,4-benzothiazepine1,1-dioxide, mp 110°-111° C.;

59)(+-)-Cis-3-Butyl-3-ethyl-2,3,4,5tetrahydro-5-(4-trifuloromethylphenyl)-1,4-benzothiazepine1,1-dioxide, mp 64°-65° C.;

60)(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(3-trifluoromethylphenyl)-1,4-benzothiazepine1,1-dioxide, mp 110°-112° C.;

61)(--)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-(3,4-difluorophenyl)-1,4-benzothiazepine1,1-dioxide, mp 205°-215° C.;

62)(+-)-Trans-3-Butyl-3-ethyl-2,3,4,5-terahydro-5-(2,4-difluorophenyl)-1,4-benzothiazepine1,1-dioxide, ml 97°-99° C.;

63)(+-)-Trans-3-isopentyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 86°-87° C.; and

64)(+-)-Cis-3-isopentyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide, mp 123°-125° C.

PHARMACEUTICAL COMPOSITION EXAMPLES

In the following Examples, the active compound can be any compound offormula (I) and/or a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof. The active compound ispreferably(-)-(RR)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepineor one of the compounds of Synthetic Examples 2 to 64.

(i) Tablet compositions

The following compositions A and B can be prepared by wet granulation ofingredients (a) to (c) and (a) to (d) with a solution of povidone,followed by addition of the magnesium stearate and compression.

Composition A

    ______________________________________                     mg/tablet                            mg/tablet    ______________________________________    (a) Active ingredient                       250      250    (b) Lactose B.P.   210      26    (c) Sodium Starch Glycollate                       20       12    (d) Povidone B.P.  15       9    (e) Magnesium Stearate                       5        3                       500      300    ______________________________________

Composition B

    ______________________________________                     mg/tablet                            mg/tablet    ______________________________________    (a) Active ingredient                       250      250    (b) Lactose 150    150      --    (c) Avicel PH 101  60       26    (d) Sodium Starch Glycollate                       20       12    (e) Povidone B.P.  15       9    (f) Magnesium Stearate                       5        3                       500      300    ______________________________________

Composition C

    ______________________________________                   mg/tablet    ______________________________________    Active ingredient                     100    Lactose          200    Starch           50    Povidone         5    Magnesium Stearate                     4                     359    ______________________________________

The following compositions D and E can be prepared by direct compressionof the admixed ingredients. The lactose used in composition E is of thedirect compression type.

Composition D

    ______________________________________                     mg/tablet    ______________________________________    Active ingredient  250    Magnesium Stearate 4    Pregelatinised Starch NF15                       146                       400    ______________________________________

Composition E

    ______________________________________                     mg/tablet    ______________________________________    Active ingredient  250    Magnesium Stearate 5    Lactose            145    Avicel             100                       500    ______________________________________

Composition F (Controlled release composition)

    ______________________________________                       mg/tablet    ______________________________________    (a) Active ingredient                         500    (b) Hydroxypropylmethylcellulose                         112    (Methocel K4M Premium)    (c) Lactose B.P.     53    (d) Povidone B.P.C.  28    (e) Magnesium Stearate                         7                         700    ______________________________________

The composition can be prepared by wet granulation of ingredients (a) to(c) with a solution of povidone, followed by addition of the magnesiumstearate and compression.

Composition G (Enteric-coated tablet)

Enteric-coated tablets of Composition C can be prepared by coating thetablets with 25 mg/tablet of an enteric polymer such as celluloseacetate phthalate, polyvinylacetate phthalate,hydroxypropylmethyl-cellulose phthalate, or anionic polymers ofmethacrylic acid and methacrylic acid methyl ester (Eudragit L). Exceptfor Eudragit L, these polymers should also include 10% (by weight of thequantity of polymer used) of a plasticizer to prevent membrane crackingduring application or on storage. Suitable plasticizers include diethylphthalate, tributyl citrate and triacetin.

Composition H (Enteric-coated controlled release tablet)

Enteric-coated tablets of Composition F can be prepared by coating thetablets with 50 mg/tablet of an enteric polymer such as celluloseacetate phthalate, polyvinylacetate phthalate,hydroxypropylmethyl-cellulose phthalate, or anionic polymers ofmethacrylic acid and methacrylic acid methyl ester (Eudragit L). Exceptfor Eudragit L, these polymers should also include 10% (by weight of thequantity of polymer used) of a plasticizer to prevent membrane crackingduring application or on storage. Suitable plasticizers include diethylphthalate, tributyl citrate and triacetin.

(ii) Capsule compositions

Composition A

Capsules can be prepared by admixing the ingredients of Composition Dabove and filling two-part hard gelatin capsules with the resultingmixture. Composition B (infra) may be prepared in a similar manner.

Composition B

    ______________________________________                     mg/capsule    ______________________________________    (a) Active ingredient                       250    (b) Lactose B.P.   143    (c) Sodium Starch Glycollate                       25    (d) Magnesium Stearate                       2                       420    Composition C                       mg/capsule    (a) Active ingredient                       250    (b) Macrogol 4000 BP                       350                       600    ______________________________________

Capsules can be prepared by melting the Macrogol 4000 BP, dispersing theactive ingredient in the melt and filling two-part hard gelatin capsulestherewith.

    ______________________________________                  mg/capsule    ______________________________________    Active ingredient                    250    Lecithin        100    Arachis Oil     100                    450    ______________________________________

Capsules can be prepared by dispersing the active ingredient in thelecithin and arachis oil and filling soft, elastic gelatin capsules withthe dispersion.

    ______________________________________                      mg/capsule    ______________________________________    (a)     Active ingredient                            250    (b)     Microcrystalline Cellulose                            125    (c)     Lactose BP      125    (d)     Ethyl Cellulose  13                            513    ______________________________________

The controlled release capsule composition can be prepared by extrudingmixed ingredients (a) to (c) using an extruder, then spheronising anddrying the extrudate. The dried pellets are coated with a releasecontrolling membrane (d) and filled into two-part, hard gelatincapsules.

    ______________________________________                      mg/capsule    ______________________________________    (a)     Active ingredient                            250    (b)     Microcrystalline Cellulose                            125    (c)     Lactose BP      125    (d)     Cellulose Acetate Phthalate                             50    (e)     Diethyl Phthalate                             5                            555    ______________________________________

The enteric capsule composition can be prepared by extruding mixedingredients (a) to (c) using an extruder, then spheronising and dryingthe extrudate. The dried pellets are coated with an enteric membrane (d)containing a plasticizer (e) and filled into two-part, hard gelatincapsules.

Composition G (Enteric-coated controlled release capsule)

Enteric capsules of Composition E can be prepared by coating thecontrolled-release pellets with 50 mg/capsule of an enteric polymer suchas cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropylmethylcellulose phthalate, or anionic polymers ofmethacrylic acid and methacrylic acid methyl ester (Eudragit L). Exceptfor Eudragit L, these polymers should also include 10% (by weight of thequantity of polymer used) of a plasticizer to prevent membrane crackingduring application or on storage. Suitable plasticizers include diethylphthalate, tributyl citrate and triacetin.

(iii) Intravenous injection composition

    ______________________________________    Active ingredient   0.200        g    Sterile, pyrogen-free phosphate buffer                        (pH 9.0) to 10                                     ml    ______________________________________

The active ingredient is dissolved in most of the phosphate buffer at35°-40° C., then made up to volume and filtered through a sterilemicropore filter into sterile 10 ml glass vials (Type 1) which aresealed with sterile closures and overseals.

(iv) Intramuscular injection composition

    ______________________________________    Active ingredient                    0.20          g    Benzyl Alcohol  0.10          g    Glycofurol 75   1.45          g    Water for Injection                    q.s. to 3.00  ml    ______________________________________

The active ingredient is dissolved in the glycofurol. The benzyl alcoholis then added and dissolved, and water added to 3 ml. The mixture isthen filtered through a sterile micropore filter and sealed in sterile 3ml glass vials (Type 1).

(v) Syrup composition

    ______________________________________    Active ingredient                   0.25           g    Sorbitol Solution                   1.50           g    Glycerol       1.00           g    Sodium Benzoate                   0.005          g    Flavour        0.0125         ml    Purified Water q.s. to 5.0    ml    ______________________________________

The sodium benzoate is dissolved in a portion of the purified water andthe sorbitol solution added. The active ingredient is added anddissolved. The resulting solution is mixed with the glycerol and thenmade up to the required volume with the purified water.

(vi) Suppository composition

    ______________________________________                          mg/suppository    ______________________________________    Active ingredient        250    Hard Fat, BP (Witepsol H15 - Dynamit NoBel)                            1770                            2020    ______________________________________

One-fifth of the Witepsol H15 is melted in a steam-jacketed pan at 45°C. maximum. The active ingredient is sifted through a 200 μm sieve andadded to the molten base with mixing, using a Silverson fitted with acutting head, until a smooth dispersion is achieved. Maintaining themixture at 45° C. the remaining Witepsol H15 is added to the suspensionwhich is stirred to ensure a homogenous mix. The entire suspension isthen passed through a 250 μm stainless steel screen and, with continuousstirring, allowed to cool to 40° C. At a temperature of 38°-40° C. 2.02g aliquots of the mixture are filled into suitable plastic moulds andthe suppositories allowed to cool to room temperature.

(vii) Pessary composition

    ______________________________________                    mg/pessary    ______________________________________    Active ingredient (63 μm)                      250    Anhydrous Dextrose                      380    Potato Starch     363    Magnesium Stearate                       7                      1000    ______________________________________

The above ingredients are mixed directly and pessaries prepared bycompression of the resulting mixture.

(viii) Transdermal composition

    ______________________________________    Active ingredient      200    mg    Alcohol USP            0.1    ml    Hydroxyethyl cellulose    ______________________________________

The active ingredient and alcohol USP are gelled with hydroxyethylcellulose and packed in a transdermal device with a surface area of 10cm².

Biological Assay

In vitro inhibition of bile acid uptake

Freshly prepared rat distal ileal brush border membrane vesicles (about200 mg vesicle protein) were incubated for 30 seconds at 24° C. in anincubation mixture comprising 10 μM ³ H taurocholate, 100 mM NaCl (orKCl) and 80 mM mannitol in 20 mM Hepes Tris pH 7.4. Each test compoundwas dissolved in ethanol (or water) and then diluted with incubationmixture to an ethanol concentration of not more than 1% v/v. Theincubation was terminated by rapid dilution and filtration and thefilter washed with an ice-cold isotonic sodium-free buffer.

The uptake of ³ H taurocholate was measured by the radioactivityremaining on the filter and converted to pmoles/mg vesicle protein. Theactive, i.e. sodium-dependent, uptake was obtained by subtracting thepassive uptake measured in 100 mM KCl from the total uptake measured in100 mM NaCl. The active uptake for each test compound was compared witha control active uptake and the results expressed at % inhibition ofbile acid uptake.

For the compound of Synthetic Example 1, the % inhibition of bile aciduptake at concentrations of 10, 3, 1 and 0.3 μM was 96, 85, 69 and 55%respectively.

I claim:
 1. A method for the preparation of a compound of formula (I)##STR19## wherein l is an integer of from 0 to 4;m is an integer of from0 to 5; n is an integer of from 0 to 2; R and R' are atoms or groupsindependently selected from halogen, nitro, phenylalkoxy, C₁₋₄ alkoxy,C₁₋₆ alkyl and --O(CH₂)_(p) SO₃ R" wherein p is an integer of from 1 to4 and R" is hydrogen or C₁₋₆ alkyl, wherein said phenylalkoxy, alkoxyand alkyl groups are optionally substituted by one or more halogenatoms; R⁴ is a C₁₋₆ straight alkyl group; and R⁵ is a C₂₋₆ straightalkyl group; which comprises: reducing the imine bond of a compound offormula (II) ##STR20## wherein l, m, R, R', R⁴, R⁵ are as hereinbeforedefined; and optionally oxidising the compound of formula (I) soobtained to the corresponding compound wherein n=1 or 2 followed byoptional conversion to a salt, solvate, or physiologically functionalderivative thereof.
 2. A compound of formula (II) ##STR21## wherein l isan integer of from 0 to 4;m is an integer of from 0 to 5; R and R' areatoms or groups independently selected from halogen, nitro,phenylalkoxy, C₁₋₄ alkoxy, C₁₋₆ alkyl and --O(CH₂)_(p) SO₃ R" wherein pis an integer of from 1 to 4 and R" is hydrogen or C₁₋₆ alkyl, whereinsaid phenylalkoxy, alkoxy and alkyl groups are optionally substituted byone or more halogen atoms; R⁴ is a C₁₋₆ straight alkyl group; R⁵ is aC₂₋₆ straight alkyl group; and salts, solvates and physiologicallyfunctional derivatives thereof.